The Nurture of Things

October 16, 2009

by Neale McDevitt

The emerging field of epigenetics is revolutionizing the study of mental health – and challenging the belief that DNA is destiny.

Like the rodents shown here, rats that are good moms can permanently change the way the genes of their offspring act, causing the pups to be calmer throughout adulthood, professors Moshe Szyf and Michael Meaney found.

Until recently, scientists saw our genetic code as an unalterable blueprint or, in the case of families with long histories of inherited illness, a life sentence. You inherit some faulty DNA from your parents, and your genes set in motion the inexorable chain of biological events that sentence you to Alzheimer’s, cancer or any number of other genetic diseases.

Not so, says Moshe Szyf, a McGill pharmacology and therapeutics professor and pioneer in the emerging field of epigenetics. Szyf, together with McGill neuroscientist Michael Meaney, has shattered the long-held belief that DNA is destiny. “This is an entirely new way of looking at, diagnosing and treating human disease,” he says. “Epigenetics will completely change the face of medicine.”

The Birth of a New Science

Moshe Szyf’s decades of groundbreaking work led to the breakthrough that put the emerging field of epigenetics on the map.

About 30 years ago, Szyf and a handful of other iconoclasts began looking at how environment and experience—in other words, nurture—could affect our genes (nature), the starting point for epigenetics. Though the benefits of exercise and a healthy diet had long been lauded as weapons to temporarily ward off those menacing genes lurking in the murkier fringes of the pool, Szyf set out to prove these and other external factors could actually permanently trigger these genes into action or silence them altogether.

After more than two decades of solo work in epigenetics, Szyf approached Meaney—now the Associate Director of Research at the Douglas Hospital Research Centre, James McGill Professor of Medicine and full professor in the Department of Psychiatry and the Department of Neurology and Neurosurgery—about collaborating. Meaney didn’t need much persuasion. “I always wanted to find out what is really at the heart of the interaction between gene and environment,” he says. “How do environmental factors literally interact with the DNA? What are the mechanisms?”

Together, they discovered that our genetic code, the actual sequential structure of our DNA, can pretty much shrug off the influence of any external environmental factors, short of massive radiation. However, the expression of individual genes within that sequence can be permanently altered by such seemingly innocuous influences as diet or how others treat us. Once triggered, a group of molecules called a methyl group attaches itself to the control centre of a gene, permanently switching on or off the manufacture of proteins that are essential to the workings of every cell in our body. In most tumours, this DNA methylation pattern has been knocked awry, leading to a gene being completely deactivated or triggered to abnormally high activity.

Now, scientific evidence is emerging that these externally driven changes in the behaviour of our genes might be passed down through the generations. For example, recent research has demonstrated that the sons of men who began smoking before puberty were more prone to obesity.

All of a sudden, we’re staring personal responsibility in the face. Not only can our bad habits or noble attempts at clean living permanently change the way our genes act within us, they could very well have a significant impact on the quality of our children’s lives.

The Breakthroughs

In 2004, Szyf and Meaney produced a study that turned conventional science on its head, definitively making the case for epigenetics. They demonstrated that rats that had received healthy doses of maternal licking as pups grew up to be calmer and more socially adept than their brethren who had mothers that weren’t nearly as attentive.

That a mother’s nurturing benefits her offspring wasn’t news. But the team’s explanation of how it came about was so novel, it verged on the heretical. Their findings proved that maternal grooming brought about a chemical change in the mechanism in the brain that regulates stress hormones—a change that persisted into adulthood.

If given quality time with caring mothers, even rats that were genetically predisposed to be frazzled calmed down and stopped overproducing stress hormones. In other words, how the young rats were treated produced permanent changes in gene expression that altered their brains—and their personalities.

So with it established that everything from smoking to nutrition can flick our genes on or off, “now the trick,” says Szyf, “is to be able to control what you activate and deactivate.” Recently, Szyf and Meaney began to do just that.

If left alone, the epigenetic changes that bad or good mothering causes in rats not only last a lifetime but can be inherited. However, the professors’ 2006 study in the Proceedings of the National Academy of Sciences showed that certain compounds could roll back these otherwise permanent epigenetic changes, calming the flood of stress hormones produced by the badly reared rats.

While there’s still a lot of uncharted water to map—which environmental factors turn which genes on and off, and what compounds can reverse unwanted epigenetic changes—the implications of these findings are enormous. Similar interventions, whether behavioural or drug therapies, could be used to combat the ravages of depression, schizophrenia and other brain disorders.

Taking Epigenetics into Mental Health

The new Neurophenotyping Centre at the Douglas Hospital, led by Claire-Dominique Walker, will help researchers untangle the complex relationship between nature and nurture, shedding light on mental health disorders.

Soon, a new Neurophenotyping Centre at the Douglas Hospital will give Szyf and Meaney cutting-edge facilities for their research. While Szyf specializes in cancer, and the new facility is geared to mental health research, findings in one area will provide a springboard for advances in other disciplines.

“Michael and I use exactly the same approaches,” says Szyf. “It’s amazing how one project actually feeds off the other. The fact that we’re working on behaviour the same time we’re working on cancer metastasis actually increases the speed each one is progressing individually.” It is a perfect example of the interdisciplinary co-operation needed to understand the multi-layered world of epigenetics.

The centre will help untangle the complex relationship between nature and nurture to shed light on many different mental health and behavioural disorders. “Most mental health problems, such as depression, schizophrenia or anxiety disorder, are caused not by a single gene but by many different genes interacting,” says Claire-Dominique Walker, Director of the Neuroscience Division at the Douglas Hospital and head of the new centre. “To this layer of complexity, you add another layer, which is the environment.”

Thanks to funding from the Ministère du Développement économique, l’Innovation et l’Exportation du Québec and the Douglas Hospital Foundation, and in association with McGill University, work on the $6-million facility will begin in March 2007. When the centre opens next fall, it will enable Quebec researchers to coordinate socio-behavioural and genetic research. The 15,000-square-foot facility will be home to some 60 researchers and up to 180 graduate students—and lots of rodents. The Neurophenotyping Centre will provide its four-legged inhabitants with larger enclosures, complete with tunnels, permitting mice and rats to exercise and create more natural social structures.

“We need to have an environment that can mimic what people live in their lives, with social stress, hierarchies, fights, aggression, etc.,” says Walker. “The enriched environments will give us much more controlled ways to test behaviour, cognitive functions and anxiety.”

While waiting for the much-needed new research space, Szyf and Meaney will continue their collaboration. “Moshe is the lateral thinker,” says Meaney. “His natural tendency is to extend this story into other systems. Mine is to make sure that we’re very focused and building a solid knowledge of the system we’re working with. In the end, we’re perfect for one another because we pull each other in complementary directions.”

This research is funded by the National Cancer Institute of Canada, the Mental Health Research Association and the Canadian Institutes of Health Research.